ICL 11.1 & 11.2: Clinical Transplantation Flashcards
what part of the blood are antibodies found?
plasma
why can’t a person with blood group O receive group A or group B blood?
because A and B have extra sugar groups on them that an O recipient would recognize as foreign
O blood groups have anti A & anti B so they will form immune complexes with RBC’s from A or B blood
why would transfusion of RhD positive blood into an RhD negative woman would make future pregnancy in the RhD negative woman a risk for pregnancy with an RhD positive fetus?
because the women would become sensitized to RhD+ and make antibodies against RhD+
so then if she has an RhD+ fetus, she will have antibodies against her kids RBCs
the first time it was find because the mom just made IgM which doesn’t cross through the placenta but with baby #2 there’s class switching and she will make IgG which DOES cross into the placenta and bind to RBCs
what type of hypersensitivity reaction is hyper acute rejection of a transplanted organ?
type II
how are RBCs different than all the other types of cells in the blood?
they have no MHC receptors!!
this is why we can easily transplant them
why do platelets have MHCI on them even though they don’t have a nucleus?
because they come from megakaryocytes which are nucleated
which cells have MHCI on them?
every single cell
**except RBCs
which cells have MHCII on them?
APCs
aka macrophages and B cells
why is blood extensively used as a transplanted tissue? 4 reasons
- no HLA molecules
- easy to give blood
- doesn’t need to last very long – only until BM makes more
- won’t be rejected by the body – won’t get immunized against another person’s RBCs because they don’t have HLA on them
how do you treat Rh disease?
anti-D
it binds to fetal cells & since it’s bound body doesn’t see free antigen so you don’t get antibody response
why type of hypersensitivity reaction is Rh disease?
type II
why type of hypersensitivity reaction can arise from blood transfusions?
type II
which organ can start to fail if you give a bad blood transfusion?
kidney
can result due to clogging of arteries by RBCs that have burst because they’re being destroyed by antibodies that are against them
extensive clotting, and you can become hypotensive
what is a cross-match test?
take donor’s blood plasma & recipient’s RBCs & mix them together
if there is no aggregation, you’re good to go and you can do the transfusion
if there is agglutination it means there are antibodies in the plasma against the donor’s RBCs
which blood cells do you use to test for HLA compatibility?
anything other than RBCs has MHCI
so we use WBC because yo can get them from a simple blood draw
if you want to test for MHCII compatibility, you use macrophages or dendritic cells
what are the important HLA loci for clinical transplantation?
HLA-A, HLA-B, & HL-DR
there’s also DP and DQ
what is the mechanism of action of hperacute rejection?
a. Hyperacute rejection occurs between HLA’s that don’t match
most people will differ in HLA
person will make antibodies against donor HLA molecules
humoral immunity will kill the donor organ – antibody mediated – Type II hypersensitivity reaction
why are mothers more likely than fathers to have a positive crossmatch with one of their children?
mothers are exposed to their fetus’s HLA
what things must match in a blood transfusion?
blood transfusions are matched for A, B, O type but NOT HLA type
there’s too many HLA combinations, it would be impossible to match
which chromosome is HLA encoded on?
chromosome 6
why do blood transfusions increase PRA?
because they increase you to more antibodies
PRA = 0 = easy to match because you don’t have a lot of antibodies
PRA = 96 = hard to match because they have antibodies against a lot of stuff from transfusions, transplants or pregnancies
why do organ transplants increase PRA?
organ transplant exposes recipients to HLAs – more antibodies in the body so harder to match to other people now
PRA measures antibodies to HLA so more HLA you have the more antibodies you’ll form – makes it harder to match
what is host vs. graft disease?
organ rejection
what is graft vs. host disease?
really only caused by BM transplants
you are transplanting a new immune system into someone that contains T cells that could attack hosts’ cells
what does ischemia cause?
ischemia causes activation of endothelium and complement leading to leukocyte infiltration and cytokine production
what type of hypersensitivity reaction is acute rejection?
type IV
it’s caused by effector T cells responding to HLA differences between donor and recipient
what are the predominant effector cells of acute transplant rejection?
CD4 TH1 helper cells directed against the grafts’ MHC class II molecules
CD8 killer cells directed against the graft’s MHC class I molecules
what is the difference between primary and secondary response to transplant antigens?
primary = 5-7 days, T cells recognize the graft as foreign
secondary response is faster because T cells have seen foreign HLA in the past and have memory cells against it
what is the mechanism underlying the direct pathway of allorecognition?
a. Organ of an allogeneic person looks like “self + X”
it doesn’t need to go inside an APC, get processed, and then presented – our body’s T cells can see it directly
do transplants have a 100% HLA match?
lol no, not even close
most patients receive HLA-mismatched transplants and need immunosuppression
you have a 25% chance of matching with a sibling 100%
what are the three categories of immunosuppressants?
- steroids with anti-inflammatory properties
- cytotoxic drugs that interfere with DNA replication and thus prohibit replication
- microbial products that interfere with T cell activation
what do steroids do?
target iL-1
which drugs are cytotoxic drugs?
tacrolimus and cyclosporin
they selectively inhibit T cell activation!
what do cytotoxic drugs do?
block IL-2 réponse in cytosol
they block calcineurin from making IL-2
what are the side effects of steroids?
- fluid retention
- weight gain
- diabetes
- loss of bone minerals
- ulcer formation
- thinning of the skin
what is the first drug of choice for treating acute rejection?
steroids
but you don’t stay on them longterm because of all the side effects
what is belatacept?
CTLA4Ig
a fusion protein that consists of the extracellular B7-binding domains of CELA4 with the Fc fragment of IgG1
newer drug used for organ transplants
how does belatacept work?
belatacept uses its CTLA4 component to bind tightly to the B7 molecules expressed by activated dendritic cells.
this interaction prevents the CD28 receptors of alloreactive T cells from binding to B7 and generating the co-stimulatory signal necessary for their activation
used for organ transplants
what is the MOA of rapamycin?
aka sirolimus
binds to FK-binding protein but doesn’t block calcineurin
it prevents signal transduction from the IL-2 receptor to the nucleus thereby preventing the T cell from entering the cell cycle and undergoing replication
if it binds to FkBP it prevents the cell from moving on past G0 phase and stops the production of t cells
how to APC activate CD4 T cells?
- APCs have MHCII receptors that bind an antigen and present them to CD4 cells
- TCR binds to MHCII-antigen complex
- CD28 on T cells binds to B7 on APC
CD40L on T cell binds to CD40 on APC
- APC releases IL-1 which activates T cell
- CD4 T cell releases IL-2 which activates CD8 T cell
this happens because TCR-MHCII/antigen binding up regulates B7 on APC
then when B7-CD28 bind, this unregulated CD40L on T cells
then when CD40L-CD40 binds this activates T cell and APC
how are CD8 T cells activated?
- CD4 T cell gets activated by binding to MHCII APC; activated CD4 cell releases IL-2 which activates CD8 t cell
- TCR on CD8 cell binds to MHCI target cell
- CD8 T cell proliferates and kills target
what do steroids do to suppress the immune system?
they block IL-1
IL-1 is what is released from APC and activates CD4 cells
what do cyclosporin and tacrolimus do to suppress the immune system?
blocks IL-2 production
IL-2 is what is released from CD4 and actives CD8 T cells
which drugs inhibit proliferation of CD8 cells?
azathioprine
mycophenolate
